RESIDUAL AND FREE C5. Residual C5 levels achieved with ALN-CC5 in healthy volunteers comparable with free. C5 levels in aHUS patients on eculizumab. â¡.
A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for Treatment of PNH and Complement-Mediated Diseases: Interim Phase 1 Study Results Anita Hill,1 Jorg Taubel,2 Jim Bush,3 Anna Borodovsky,4 Noriyuki Kawahata,4 Helen Mclean,4 Christine Powell,4 Prasoon Chaturvedi,4 Garvin Warner,4 Pushkal Garg,4 Benny Sorensen,4 and Nader Najafian4 1St
James' Institute of Oncology; Leeds Teaching Hospitals, Leeds, UK; 2St George's University of London, London, UK; 3Covance Clinical Research Unit, Leeds, UK; 4Alnylam Pharmaceuticals, Cambridge, USA
Part B (MAD): Serum C5 knockdown
BACKGROUND
Safety and Tolerability*
PNH
ALN-CC5 appears generally well tolerated in healthy volunteers
• Bone marrow defect due to acquired PIG-A gene mutation leading to deficiency of GPIanchored surface proteins that protect red blood cells against complement mediated cell lysis • Eculizumab is an anti-C5 monoclonal antibody approved for treatment of PNH and aHUS • Current Treatment Challenges
Part A: Single Ascending Dose (SAD)
‒
Wide inter-individual variation in clearance of eculizumab with discrepancy between labeled effective trough level (35 mcg/mL) vs expert recommendations of >150 mcg/mL1-3
AE by Preferred Term occurring in ≥10% of patients, n (%) Nasopharyngitis
50 mg N=4 0 0 0
1 0
0 0
2 1
2 1
5 (25%) 2 (10%)
Nausea
0
0
0
2
0
2 (10%)
ALN-CC5
Injection site pain
0
0
0
2
0
2 (10%)
•
Seasonal allergy
0
0
0
1
1
2 (10%)
siRNA conjugated to N-acetylgalactosamine (GalNAc) ligand utilizing enhanced stabilization chemistry (ESC) ‒
• •
• •
Significantly improved potency and durability; wide therapeutic index
Efficient delivery to hepatocytes following SC administration 200 mg/mL solution
•
• • •
Serum C5 levels after multiple doses of ALN-CC5 in healthy human volunteers Residual C5 levels measured using validated LCMS assay Maximum % inhibition residual C5: 99%
All reported AEs mild or moderate in severity; 3 possibly drug-related treatment •
‒
ALN-CC5 PHASE 1 STUDY DESIGN
•
Concentration-effect relationship for reduction in free C5 in aHUS patients Free C5 measured using validated electrochemiluminescence immunoassay Maximum % inhibition free C5: 93.5%
ALN-CC5 and C5 levels (mcg/mL)
No SAEs and no discontinuation due to AEs Total of 29 AEs observed ‒
•
•
All cohorts (N=20) 5 (25%)
Headache Influenza-like illness
• Unmet need for new complement inhibitors remains
Eculizumab and free C5 levels (mcg/mL)4
Serum C5 knockdown following 5 weekly doses of ALN-CC5
Part A: Single Ascending Dose (SAD) 20 healthy volunteers dosed with ALN-CC5 or Placebo (3:1); single SC injection 200 mg 400 mg 600 mg 900 mg N=4 N=4 N=4 N=4 2 2 1 0
RESIDUAL AND FREE C5
• Maximum C5 knockdown relative to baseline up to 99% • Mean maximum (± SEM): 98 ± 0.5% • Mean (± SEM): 98 ± 0.3% at Day 112 (200 mg q1wk x5)
Possibly drug-related AEs: nasopharyngitis, injection site pain, and injection site rash (coded as rash)
Part B (MAD): Complement Inhibition
ISRs seen in 2 subjects – all mild and transient
• • •
No clinically significant changes in vital signs, EKG, physical exams and clinical laboratories (hematology, biochemistry, coagulation and urinalysis)
Part B: Multiple Ascending Dose (MAD)
Maximum CAP inhibition relative to baseline up to 97% Mean maximum (± SEM): 95 ± 1.0% CAP activity comparable to homozygous C5 deficient subjects5 in MAD 200 mg & 400 mg
Part B: Multiple Ascending Dose (MAD) AE by Preferred Term occurring in ≥10% of patients, n (%)
12 healthy volunteers dosed with ALN-CC5 or Placebo (3:1); weekly ×5 100 mg n=4
200 mg N=4
400 mg N=4
All cohorts N=12
1 0 0
1 3 1
1 0 1
3 (25%) 3 (25%) 2 (17%)
Headache Nasopharyngitis Vulvovaginal Candidiasis
• •
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Primary: Safety and tolerability Secondary & Exploratory: Pharmacokinetics; Pharmacodynamics - C5 levels, Complement activity assessment (CAP, CCP, Sheep RBC hemolysis), LDH (Part C), Quality of life (Part C)
Complement Assay Benchmarks from Select Published Literature Assay
Disease
Values reported in literature
Notes
Free C5 (Electrohemiluminescence immunoassay)
aHUS (patients treated with eculizumab)
93.5%4 (Max % C5 inhibition)
Results from clinical study of aHUS patients treated with eculizumab at 900 mg (4xqW) and maintained at 1200 mg q2W 4 (pediatrics dosed per body weight) Studies : C08-002A/B, C08-003A/B, C09-001r4
CAP/CCP (Wieslab ELISA assays)
Genetic C5b-9 complement deficiency
